Dual transcriptional programs coordinate lipogenic and membrane stress responsive programs in C. elegans

双转录程序协调线虫的脂肪生成和膜应激反应程序

基本信息

批准号：
10376264
负责人：
Amy Karol Walker
金额：
$ 22.79万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10376264
关键词：
Affect Age Aging Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animal Model Animals Binding Biochemical Biochemistry Biological Assay Caenorhabditis elegans Calories Carbon Cell Aging Cell Line Cell physiology Cells Cellular Stress Cellular biology Complement Data Egg Yolk Proteins Endoplasmic Reticulum Environment Enzymes Epigenetic Process Esthesia Financial compensation Genetic Genetic Screening Genetic Transcription Golgi Apparatus Guanosine Triphosphate Phosphohydrolases HMGB1 Protein Health Homeostasis Human In Vitro Individual Intestines Investigation Lecithin Light Link Lipid Bilayers Lipids Lipodystrophy Longevity Mammalian Cell Measures Membrane Metabolic Metabolic Diseases Metabolic Pathway Metabolism Mitochondria Modeling Modification Molecular Mutation N-terminal Nature Neurodegenerative Disorders Nutrient Nutritional Organelles Orthologous Gene Output Parkinson Disease Pathway interactions Patients Peptide Hydrolases Phenotype Phospholipids Play Process Production Property Proteins Regulation Role S-Adenosylmethionine SRE-1 binding protein Signal Transduction Site Source Stress Tissues arm base biological adaptation to stress experimental study human disease in vivo insight lipid metabolism metabolic phenotype metabolomics mutant paralogous gene programs repaired response transcription factor

项目摘要

Metabolism can affect the aging process through many mechanisms. The effects of calorie levels and the sensation of nutrient sources are powerful regulators. Other metabolic pathways may affect aging by acting as signaling or transcriptional regulators. The 1 carbon cycle has multiple links to aging, particularly through the production of the methyl donor S-adenosylmethionine (SAM). SAM is critical for epigenetic modification, which can affect many cellular processes, including aging. SAM is also important for the production of a phospholipid, phosphatidylcholine (PC), which is a major membrane component. We propose to study how one 1CC metabolite, PC, impacts aging though it’s role in a membrane stress pathway. Using a long-lived C. elegans model (sams-1) and human cell-based assays, we found that lowering PC induces a stress response in the Golgi, limiting the GTPase ARF-1.2/ARF1, which is a critical regulator of Golgi function. One effect of this stress response is the maturation of a membrane-intrinsic transcription factor, SBP-1/SREBP-1, to restore lipid homeostasis. We also found that a compensatory program is upregulated that produces an alternative ARF, arf- 1.1. to support Golgi function. We have identified at least one transcription factor, LET-607, which is also intrinsic to the membrane, as a regulator of this process. Thus, the Golgi stress response has multiple transcriptional outputs that play specific roles in correcting organelle misfunction. Finally, Golgi stress may be important in multiple neurodegenerative diseases, suggesting our studies could have a broad impact outside the aging field. Our proposal is based on data from multiple genetic screens, metabolomic studies, and other unbiased approaches. Next, our plan is to use a combination of cell biology, genetics and biochemistry several key questions. First, we will explore the basic cell biology of the Golgi stress response, which is not well understood. Second, we will determine how the LET-607 transcription factor is regulated during the stress response. These experiments will be complemented by our investigation on the molecular and biochemical basis explaining how ARF-1.1 can function when membrane conditions limit ARF-1.2. Finally, we have found that ARF-1.2 selectively disappears from the intestine in aging C. elegans. Because regulation of yolk secretion has important connections to aging, it is important to understand what regulates this loss of ARF-1.2 and how it might impact aging in sams-1 animals. Metabolites such as SAM and PC may have distinct roles in aging and stress in a variety of contexts, as these molecules can contribute to a variety of different processes. By delineating molecular mechanisms downstream of SAM and PC that affect membrane properties, we will uncover how specific aspects of 1 carbon and lipid metabolism drive changes in aging and stress.

新陈代谢可以通过多种机制影响衰老过程，热量水平和热量的影响。营养来源的感觉是强大的调节剂，其他代谢途径可能通过充当影响衰老的方式。 1 碳循环与衰老有多种联系，特别是通过甲基供体 S-腺苷甲硫氨酸 (SAM) 的产生对于表观遗传修饰至关重要，它可以影响许多细胞过程，包括衰老，对于 SAM 的产生也很重要。磷脂，磷脂酰胆碱（PC），它是一种主要的膜成分，我们建议研究其中之一。 1CC 代谢物 PC 通过在膜应激途径中发挥作用而影响衰老。在线虫模型 (sams-1) 和基于人类细胞的检测中，我们发现降低 PC 会诱导应激反应高尔基体，限制 GTPase ARF-1.2/ARF1，这是高尔基体功能的一个关键调节因子。应激反应是膜内转录因子 SBP-1/SREBP-1 的成熟，以恢复脂质我们还发现补偿计划被上调，产生替代性 ARF，arf-。 1.1. 支持高尔基体功能我们已经鉴定出至少一种转录因子 LET-607，它也是作为该过程的调节者，高尔基体具有内在的应激反应。最后，在纠正细胞器功能障碍中发挥特定作用的转录输出可能是高尔基体应激。在多种神经退行性疾病中很重要，这表明我们的研究可能会在其他领域产生广泛的影响老龄化领域。我们的建议基于来自多个基因筛查、代谢组学研究和其他公正的数据接下来，我们的计划是结合细胞生物学、遗传学和生物化学的几个关键方法。首先，我们将探讨高尔基体应激反应的基本细胞生物学，目前尚不清楚。其次，我们将确定 LET-607 转录因子在应激过程中是如何受到调节的。我们对分子和生化基础的研究将补充这些实验。解释当膜条件限制 ARF-1.2 时 ARF-1.1 如何发挥作用最后，我们发现了这一点。 ARF-1.2 在衰老的秀丽隐杆线虫肠道中选择性消失，因为卵黄分泌的调节已发生。由于 ARF-1.2 的丢失与衰老有重要联系，因此了解是什么调节了 ARF-1.2 的丢失以及它是如何发生的非常重要。可能会影响 sams-1 动物的衰老。 SAM 和 PC 等代谢物可能在衰老和衰老过程中发挥不同的作用。在各种情况下都会产生压力，因为这些分子可以促进各种不同的过程。描述 SAM 和 PC 下游影响膜特性的分子机制，我们将揭示 1 碳和脂质代谢的特定方面如何驱动衰老和压力的变化。